Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-05
2002-02-19
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S377000, C514S394000, C514S398000, C514S399000, C514S424000, C548S193000, C548S233000, C548S310100, C548S331500, C548S341100, C548S558000
Reexamination Certificate
active
06348482
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of transfer ribonucleic acid (tRNA) synthetase inhibitors, their preparation and their use as antimicrobial agents.
BACKGROUND OF THE INVENTION
Aminoacyl tRNA synthetases (aaRS) are a family of essential enzymes that are found in virtually every biological cell and are responsible for maintaining the fidelity of protein synthesis. They specifically catalyze the aminoacylation of tRNA in a two step reaction:
amino acid (AA)+ATP=>AA-AMP+PPi
AA-AMP+tRNA=>tRNA-AA+AMP
The enzyme binds adenosine triphosphate (ATP) and its specific amino acid to catalyze formation of an aminoacyl adenylate complex (AA-AMP) with concomitant release of pyrophosphate (PPi). In the second step, the amino acid is transferred to the 2′ or 3′ terminus of the tRNA yielding “charged” tRNA and adenosine monophosphate (AMP). The charged tRNA delivers the amino acid to the nascent polypeptide chain on the ribosome.
There are at least twenty essential enzymes in this family for each organism. Inhibition of any of the essential tRNA synthetases disrupts protein translation, ultimately resulting in growth inhibition. Pseudomonic acid A, an antibacterial agent currently used in human therapy, provides clear evidence of the utility of tRNA synthetase inhibitors as useful pharmaceuticals. Pseudomonic acid A binds to one particular tRNA synthetase, isoleucyl tRNA synthetase, and inhibits isoleucyl adenylate formation in several Gram positive bacterial pathogens such as
Staphylococcus aureus,
resulting in the inhibition of protein synthesis, followed by growth inhibition.
Novel synthetic compounds that target tRNA synthetases offer clear advantages as useful therapeutic agents to curb the threat of drug resistance. Drug resistance allows a pathogen to circumvent the biochemical disruption caused by an antimicrobial agent. This resistance can be a result of a mutation that has been selected for and maintained. Pathogens in the environment have had repeated exposure to current therapeutics. This exposure has led to the selection of variant antimicrobial strains resistant to these drugs. Novel synthetic antimicrobial agents, therefore, would be expected to be useful to treat drug resistant pathogens, since the pathogen has never been exposed to the novel antimicrobial agent. The development of compounds or combinations of compounds targeting more than one tRNA synthetase is also advantageous. Accordingly, inhibition of more than one enzyme should reduce the incidence of resistance since multiple mutations in a pathogen would be required and are statistically rare.
SUMMARY OF THE INVENTION
The present invention discloses novel compounds which inhibit tRNA synthetases and have efficacy, including whole cell killing, against a broad spectrum of bacteria and fungi. Described herein are compounds that exhibit tRNA synthetase inhibition.
The present invention comprises, in one aspect, compounds of Formula I.
Group Ar of Formula I is selected from aryl or heteroaryl. Preferably, Ar is aryl, more preferably, substituted phenyl, even more preferably, 2,4-dichlorophenyl.
Each of substituents R
1
, R
2
, R
3
, and R
4
of Formula I is independently hydrido, alkyl, cyano, heteroaryl, hydroxy, amino, acylamino, halo, alkoxy, aryloxy, carboxyamido, alkenyl, cycloalkyl, heterocyclyl, acyl, acyloxy, carboalkoxy, carboxy, thio, sulfinyl, sulfonyl or sulfoxy, provided that at least two of R
1
, R
2
, R
3
and R
4
is hydrido. Preferably, each of substituents R
1
, R
2
, R
3
and R
4
is independently selected from hydrido, carboxyl, alkyl, carboxyamido, N-acylaminosulfonyl, N-sulfonylcarboxyamido, and alkoxy. More preferably, each of substituents R
1
, R
2
, R
3
and R
4
is independently selected from —(CH
2
)
m
CO
2
H—, —(CH
2
)
m
CONHCH(R
9
)CO
2
H—, —CONHSO
2
R
10
—, and —O(CH
2
)
m
CO
2
H; wherein each of R
9
and R
10
is independently selected from alkyl and halo substituted alkyl; wherein m is selected from 0, 1 and 2.
Each of substituents R
5
, R
6
, R
7
and R
8
is independently hydrido or lower alkyl, preferably hydrido.
Group Het of Formula I is selected from
wherein X is selected from N or CR
11
; wherein Y is selected from NH, S or O; wherein Z is selected from N or CR
12
; wherein each of R
11
, R
12
, R
13
, and R
14
is independently selected from nitro, halo, hydroxy, lower amino, lower alkyl, lower alkoxy, aryloxy, lower carboalkoxy, sulfinyl, sulfonyl, carboxy, lower thio, and sulfoxy; and wherein each of R
15
, R
16
, and R
17
is selected from hydrido, alkyl, aryl, nitro, amino, sulfonyl or sulfinyl. Preferably, Het is
The invention also embraces pharmaceutically-acceptable salts of the forgoing compounds.
A further aspect of the invention comprises using a composition comprising the compound(s) of Formula I to inhibit a tRNA synthetase and in particular, to modulate the growth of bacterial or fungal organisms in mammals, a plant or a cell culture.
Yet another aspect of the invention involves a method of inhibiting the growth of microorganisms. The method involves exposing the microorganism to a compound of the invention, preferably a compound of Formula I, under conditions whereby a therapeutically effective amount of the compound enters the microorganism. The method is useful for inhibiting the growth of microrganisms in vivo and in vitro.
Another aspect of the invention is a pharmaceutical composition comprising the compound(s) of the invention and, in particular, the compounds of Formula I, useful in the treatment of microbial infections, e.g., bacterial infections, fungal infections. A related aspect of the invention is a method of making a medicament which involves placing a compound(s) of the invention, preferably a compound of Formula I, in a suitable pharmaceutically acceptable carrier.
These and other aspects of the invention will be more apparent in reference to the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
Molecular terms, when used in this application, have their common meaning unless otherwise specified. The term “hydrido” denotes a single hydrogen atom (H). The term “acyl” is defined as a carbonyl radical attached to a hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycyl, aryl or heteroaryl group, examples of such radicals being formyl, acetyl and benzoyl. The term “amino” denotes a nitrogen radical containing two substituents independently selected from the group consisting of hydrido, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferred amino radicals are NH
2
radicals and “lower amino” radicals, whereby the two substituents are independently selected from hydrido and lower alkyl. A subset of amino is “alkylamino”, whereby the nitrogen radical contains at least 1 alkyl substituent. Preferred alkylamino groups contain alkyl groups that are substituted, for example, with a carboalkoxy group. The term “acyloxy” denotes an oxygen radical adjacent to an acyl group. The term “acylamino” denotes a nitrogen radical adjacent to an acyl, carboalkoxy or carboxyamido group. The term “carboalkoxy” is defined as a carbonyl radical adjacent to an alkoxy or aryloxy group. The term “carboxyamido” denotes a carbonyl radical adjacent to an amino group. A subset of carboxyamido is “N-sulfonylcarboxyamido” which denotes a carbonyl radical adjacent to an N-sulfonyl-substituted amino group. The term “halo” is defined as a bromo, chloro, fluoro or iodo radical. The term “thio” denotes a sulfur radical adjacent to a substituent group selected from hydrido, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, such as, methylthio and phenylthio. Preferred thio radicals are “lower thio” radicals containing lower alkyl groups.
The term “alkyl” is defined as a linear or branched, saturated radical having one to about ten carbon atoms unless otherwise specified. Preferred alkyl radicals are “lower alkyl” radicals having one to about five carbon atoms. One or more hydrogen atoms can also be replaced by a substitutent group selected from acy
Finn John
Hammond Milton L.
Hill Jason
Keith Dennis
Leeman Aaron H.
Daniel Mark R.
Hunter, Jr. James M.
Merck & Co. , Inc.
Seaman D. Margaret
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